Parenteral therapeutical system comprising drug cell

ABSTRACT

A formulation chamber is disclosed comprising a wall surrounding a lumen containing a device for delivering a beneficial agent. The chamber has an inlet for admitting a fluid into the chamber and an outlet for letting an agent formulation leave the chamber. The chamber is adapted for parenteral use including intravenous delivering for delivering an agent formulation to a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. Pat. Appln. Ser. No. 06/797,307filed Nov. 12, 1985 which appln. Ser. No. 06/797,307 is a cont-in-partof U.S. Appln Ser. No. 06/702,973 filed Feb. 19, 1985, now U.S. Pat. No.4,740,201, which appln. Ser. No. 06/702,973 is a div. of U.S. Appln.Ser. No. 06/310,047 filed Oct. 9, 1981, now U.S. Pat. No. 4,511,353issued Apr. 16, 1985, which appln. Ser. No. 06/310,047 is a cont-in-partof U.S. Appln. Ser. No. 06/283,077 filed July 13, 1981 now abandoned.

This appln. Ser. No. 06/797,307 also is a cont-in-part of U.S. Appln.Ser. No. 06/664,802 filed Oct. 25, 1984, now U.S. Pat. 4,790,820, whichappln. Ser. No. 06/664,802 is a cont-in-part of U.S. Appln. Ser. No.06/576,929 filed Feb. 3, 1984, now abandoned, which Appln Ser. No.06/576,929 is a div. of U.S. Appln. Ser. No. 06/377,831 filed May 13,1984, now U.S. Pat. No. 4,439,183 issued Mar. 27, 1984, which Appln.Ser. No. 06/377,831 is a cont-in-part of U.S. Appln. Ser. No. 06/310,047filed Oct. 9, 1981, now U.S. Pat. No. 4,511,353. which Appln. Ser. No.06/310,047 is a cont-in-part of U.S. Appln. Ser. No. 06/283,077 filedJuly 13, 1981 now abandoned.

This appln. Ser. No. 06/797,307 also is a cont-in-part of U.S. Appln.Ser. No. 06/588,165 filed Mar. 9, 1984, which Appln. Ser. No. 06/588,165is a cont-in-part of U.S. Appln. Ser. No. 06/312,491 filed Oct. 19,1981, now U.S. Pat. No. 4,552,555 issued Nov. 12, 1985, which Appln.Ser. No. 06/312,491 is a cont-in-part of U.S. Appln. Ser. No. 06/289,082filed July 31, 1981 now abandoned.

The above applications are incorporated herein by reference and benefitis claimed of their filing dates. All of these applications are assignedto the ALZA Corporation of Palo Alto, CA.

Other related cases assigned to ALZA Corporation are: U.S. Appln. Ser.No. 702,291 filed Feb. 15, 1985; U.S. Appln. Ser. No. 702,293 filed Feb.15, 1985; U.S. Appln. Ser. No. 702,292 filed Feb. 15, 1985; U.S. Appln.Ser. No. 701,720 filed Feb. 14, 1985; U.S. Appln. Ser. No. 701,729 filedFeb. 14, 1985; U.S. Appln. Ser. No. 701,730 filed Feb. 14, 1985; U.S.Appln. Ser. No. 702,273 filed Feb. 15, 1985 and U.S. Appln. Ser. No.702,171 filed Feb. 15, 1985, all of which are divs. of U.S. Appln. Ser.No. 319,047, now U.S. Pat. 4,511,353 issued Apr. 16, 1985; U.S. Appln.Ser. No. 587,745 filed Mar. 9, 1984, a cont. of U.S. Appln. Ser. No.310,047; U.S. Appln. Ser. No. 577,241 filed Feb. 3, 1984, now U.S. Pat.No. 4,548,598 issued Oct. 22, 1985; U.S. Appln. Ser. No. 576,572 filedFeb. 3, 1984, now U.S. Pat. 4,521,211 issued June 4, 1985 and U.S.Appln. Ser. No. 576,966 filed Feb. 3, 1984, abn., all of which are divs.of U.S. Appln. Ser. No. 377,831, now U.S. Pat. 4,439,183 issued Mar. 27,1984.

FIELD OF THE INVENTION

This invention pertains to an intravenous delivery system, and to a drugformulation chamber comprising an agent delivery system. The inventionrelates also to a method of administering intravenously an agentformulation, and to a method for forming the agent formulation.

BACKGROUND OF THE INVENTION

The parenteral administration of medical liquids is an establishedclinical practice. The liquids are administered particularlyintravenously, and the practice is used extensively as an integral partof the daily treatment of medical and surgical patients The liquidscommonly administered include blood and blood substitutes, dextrosesolution, electrolyte solution and saline. Generally the liquids areadministered from an intravenous delivery system having a containersuspended above the patient, with the liquid flowing through a catheterhypodermic needle set to the patient.

The administration of liquids intravenously is a valuable and importantcomponent that contributes to the optimal care of the patient; however,it does not provide a satisfactory means and method for administeringconcomitantly therewith a beneficial agent. Presently a beneficial agentis administered intravenously by (2) temporarily removing theintravenous system administering the agent to the patient followed byreinserting the intravenous system into the patient; (2) an agent isadded to the liquid in the container and then carried by the flow of theliquid to the patient; (3) agent is added to a liquid in a separatecontainer called a "partial fill" that is connected to the primaryintravenous line through which line the agent is carried by the flow ofliquid to the patient; (4) agent is contained in a piggyback vial intowhich is introduced an intravenous fluid, with the vial subsequentlyconnected to the primary line through which the agent is administered toa patient, or, (5) agent is administered by a pump that exerts a forceon a liquid containing agent for intravenously administering the liquidcontaining the agent. While these techniques are used, they have majordisadvantages. For example, they often require preformulation of theagent medication by the hospital pharmacist or nurse, the requireseparate connections for joining the primary intravenous line thatfurther complicates intravenous administration, the use of pumps canproduce pressures that can vary at the delivery site and the pressurecan give rise to thrombosis, and the rate of agent delivery to thepatient often is unknown as it is not rate-controlled agent delivery,but delivery dependent on the flow of fluid administered over time. Inview of this presentation it is apparent a critical need exists in thefield of intravenous delivery for a rate-controlled means foradministering a beneficial agent in intravenous delivery systems.

DISCLOSURE OF THE INVENTION

Accordingly, a principal object of this invention is to provide anintravenous delivery system comprising means for admitting an agent at arate controlled by the means into an intravenous fluid for optimizingthe care of a human whose prognosis benefits from intravenous delivery.

Another object of the invention is to provide an intravenous deliverysystem comprising an agent formulation chamber comprising an agentdelivery device for admitting an agent at a rate controlled by thedelivery device into an intravenous fluid for optimizing the care of apatient on intravenous therapy.

Another object of the invention is to provide an agent formulationchamber adapted for use with an intravenous delivery system and whichchamber houses agent delivery means for admitting an agent at acontrolled rate into an intravenous fluid admitted into the chamber.

Another object of the invention is to provide an intravenous therapeuticsystem comprising a container and a drug formulation chamber whichchamber houses a device for delivering a drug at a rate governed by thedevice into a medical fluid that flows from the container into thechamber and then to a drug recipient.

Another object of the invention is to provide an intravenous therapeuticsystem comprising a container and a drug formulation chamber that housesa delivery system for forming an intravenously acceptable fluid drugformulation in situ at a rate governed by the system releasing the drugcombined with controlling the volume of fluid flowing through theformulation chamber for mixing the drug with the intravenouslyacceptable medical fluid that flows from the container into the chamberand, hence, to a drug recipient.

Another object of the invention is to provide an intravenous formulationchamber equipped with a drug releasing member for (1) formulating anintravenously administrable fluid drug formulation in the formulationchamber by (2) adding a drug to an intravenous medical fluid that entersthe chamber and is a pharmaceutically acceptable carrier for the drug at(3) a rate governed by the combined operations of the member releasingthe drug and the rate of fluid flow through the chamber.

Another object of the invention is to provide a formulation chamberhousing a delivery device containing a drug that forms on its releasefrom the device a drug formulation with fluid that enters the chamber bythe combined operations of the device releasing the drug and the rate offluid flow through the chamber.

The invention concerns both an intravenous delivery system comprising anagent formulation chamber and the agent formulation chamber. The chambercontains an agent formulation, wherein (1) an agent originally presentin a delivery means present in the chamber is released at a ratecontrolled by the delivery means. The agent on its release is formulatedin situ with an intravenous fluid that enters the chamber with the agentreleased at a controlled rate that is preferably essentially independentof the volume rate of an intravenous fluid entering the formulationchamber, and the infused into a recipient. The expression, "deliverymeans", as used herein, generically denotes a means or a system forstoring and delivering a beneficial agent at a rate controlled by themeans to establish a beneficial or a therapeutic need. The means, inpresently preferred embodiments, are designed and manufactured as anagent delivery device, which device also is a rate-controlled dosageform of the agent. The delivery device or dosage forms stores an amountof agent for executing a prescribed beneficial program, and it providesfor the preprogrammed, unattended delivery of a beneficially or atherapeutically effective amount of the agent to produce a beneficial ortherapeutic result. The delivery device, or the dosage form, are adaptedfor easy placement and retention in the formulation chamber, and theysubstantially maintain their physical and chemical integrity duringtheir release history The formulation chamber contain an agentformulation, wherein (2) agent in another embodiment is originallypresent in a pharmaceutical form that forms a fluid formulation in thechamber that is released from the formulation chamber by release ratemeans present in the formulation chamber The expression, "beneficialagent" generically denotes a substance that produces a beneficial or atherapeutic result, such as a drug, a carbohydrate, and/or the like. Theterm, "fluid or liquid" denotes a fluid that can be administeredparenterally, including intravenously, comprising pharmaceuticallyacceptable fluids that are also a pharmaceutically acceptable carrierfor the agent. The invention also is an intravenous therapeutic systemfor administering a liquid drug formulation, wherein the liquid drugformulation is formulated in situ. The intravenous delivery systemgenerically comprises in combination:

(a) a container for storing a pharmaceutically acceptable liquid carrierfor the agent;

(b) an agent formulation chamber comprising: an inlet that permitscommunication with the container to let a liquid carrier flow from thecontainer into the formulation chamber; and, an outlet through which theliquid exits the chamber;

(c) an agent delivery means in the chamber, which means is arate-controlled dosage form of agent that is in communication with aliquid flowing through the chamber, and wherein, when in operation, themeans releases the agent into the liquid at a predetermined rate that issubstantially independent of the volume rate of liquid flow flowingthrough the chamber; or,

(d) an agent in the chamber in a pharmaceutically acceptable form thatis in communication with a liquid flowing through the chamber and arelease rate film in the chamber, that release the agent and fluid fromthe chamber; and,

(e) a conduit that communicates with the chamber outlet and extends toan infusion recipient site. The agent formulation chamber generallycomprises means for housing and delivering an agent at a rate-controlledby the means over time, or an agent and a release rate film means thatrelease agent from the chamber over time.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the Figures are asfollows:

FIG. 1 is a perspective view showing an embodiment of the inventioncomprising an intravenous delivery system in use;

FIGS. 2a and 2b are perspective views of an agent formulation chamberprovided by the invention with the formulation chamber housing a meansfor delivering an agent which means is manufactured as an agent deliverydevice;

FIG. 3 is a view of an agent formulation chamber containing an agentdelivery device comprising an agent release rate controlling membranesurrounding a reservoir containing agent;

FIG. 4 is a view of an agent formulation chamber containing a deliverydevice comprising a release rate controlling membrane surrounding adifferent reservoir containing agent;

FIG. 5 is a view of an agent formulation chamber containing a deliverydevice comprising a microporous membrane surrounding a reservoircontaining agent;

FIG. 6 is a view of an agent formulation chamber containing a deliverydevice comprising a matrix containing agent:

FIG. 7 is a view of an agent formulation chamber containing an agentdelivery device comprising a microporous matrix containing an agent;

FIG. 8 is a view of an agent formulation chamber containing a deliverydevice comprising depots of agent;

FIG. 9 is a view of an agent formulation chamber containing a deliverydevice comprising a housing and driving member surrounding a flexiblecontainer;

FIG. 10 is an embodiment of the invention illustrating an agentformulation chamber in fragmentary view;

FIG. 11 is a sectional, fragmentary view of the parts of the embodimentshowing in FIG. 10;

FIG. 12 is an enlarged, partly sectional view of another formulationchamber;

FIG. 13 is an enlarged, partly sectional view of still anotherembodiment of an agent formulation chamber housing a delivery device;

FIG. 14 is a view of a formulation chamber housing a delivery systemcomprising a multiplicity of tiny timed pills;

FIG. 15 is a view of a formulation chamber seen in opened sectiondepicting the chamber housing a delivery system comprising a pluralityof tiny capsules containing a beneficial agent:

FIG. 16 is a view of a formulation chamber housing a delivery systemcomprising a multiplicity of hollow fibers filled with beneficial agent:

FIG. 17 is a view of a formulation chamber housing a delivery systemcomprising a plurality of solid fiber filled with beneficial agent;

FIG. 18 is a view of a formulation chamber housing a delivery systemcomprising a drug delivery system consisting of a bioerodible polymerhousing beneficial agent;

FIG. 19 is an opened view of a formulation chamber housing a pluralityof ion-exchange member with active agent ionically bonded thereto;

FIG. 20 is an opened view of a beneficial agent formulation chambercomprising a beneficial agent and a flow controlling membrane forgoverning the rate of fluid passage and the accompanying rate of drugpassage through the chamber;

FIG. 21 is an opened view of a formulation chamber comprising abeneficial agent, a flow controlling membrane, and a filter;

FIG. 22 is an opened view of a formulation chamber manufactured with anagent containing compartment;

FIG. 23 is a graph showing a typical relationship between the mass rateof agent administration and the volume flow rate of intravenous fluid tothe patient that results from use of the invention; and,

FIG. 24 is a graph that indicates the time required for the deliveryrate to reach a steady state of delivery.

In the specification and drawings like parts in related Figures areidentified by like numerals. The terms appearing earlier in thespecification and in the description of the drawings are describedhereafter in the disclosure.

MODES FOR CARRYING OUT THE INVENTION

FIG. 1 illustrates one operative embodiment of the invention, comprisingan intravenous delivery system, generally designated by the numeral 10.System 10 comprises a container 12 that contains a liquid 13 adapted forparenteral, including intravenous, administration, and an administrationset, generally designated 14. The liquid 13 in container 12 willtypically be a medical fluid, a sterile solution such as an aqueoussolution of dextrose, saline, and electrolytes. It must be apharmaceutical vehicle for intravenous administration and for an agentthat is to be administered to a recipient. Container 12 is manufacturedfrom glass or plastic, and preferably of the no air-tube vacuum typeand, thus, it is used with an administration set that has an air inletfilter. Other types of containers such as the air-tube vacuum type, orthe non-vented type can be used for the intended purpose. Thesealternative containers do not require an air filter in theadministration set. Container 12 can be rigid, semi-rigid or flexible instructure, and it is usually adapted to be hung neckdown from a hanger15 by a handle or strap 16 that connects or surrounds container 12. Theneck of the container 12 is covered by a closure 17, generally made ofrubber and air-tight.

Administration set 14 and container 12 are interconnected by piercingclosure 17 with one end of a needle or hollow spike 18 attached to orformed as a part of administration set 14. Needle 18 is equipped with aside air vent 19. The other end of needle 18 is enlarged and fits snuglyinto a drip chamber 22. Drip chamber 22 traps air contained in the setand facilitates adjusting the flow rate of intravenous fluid 13 fromcontainer 12 as the flow proceeds drop wise. The outlet at the bottom ofdrip chamber 22 is connected to a first segment of tubing 23 which fitsinto inlet 24 of agent formulation chamber 25, the details of which arepresented in subsequent figures. A second segment of tubing 23 connectsto outlet 26 of agent formulation chamber 25 and leads to bacterialfilter 27. A third segment of tubing 23 extends from filter 27 to aninfusion agent receptor site, terminating in an adapted-needle assembly28 that is inserted into a vein of a warm-blooded animal 29, shown as ahuman patient's arm. An affixation means 32, usually a piece of tape,holds adapter-needle assembly 28 firmly in place on the recipient's arm.The administration set can also include a pair of tubing clamps 33 and34 located on either side of formulation chamber 25 that may be used togovern or stop the flow rate of intravenous fluid through theintravenous therapy system.

Agent formulation chamber 25, as seen in FIGS. 2a and 2b, is the uniquecomponent of the intravenous delivery system. Agent formulation chamber25 is sized and adapted for use in intravenous systems, it isself-contained, self-powered and amenable to low cost manufacturing. Theuse of the agent formulation chamber with an agent delivery meanstherein does not require any reconstitution or admixture prior to use.Agent formulation chamber 25, hereafter referred to as formulationchamber 25, in the illustrated embodiment, comprises a wall 9 thatsurrounds and defines an internal space 38. Chamber 25 has an inlet 24adapted and sized for placing chamber 25 into an intravenous deliverysystem, and it has an outlet 26 also adapted and sized for placing thechamber in the system. Inlet 24 and outlet 26 are made for receivingtube 23. Chamber 25, is manufactured of glass, plastic or the like, andas illustrated it is made of a transparent material for illustrating itsstructure and a device housed therein. In the embodiment shown, chamber25 comprises a pair of interfitting housing halves 35 and 36 forcontaining agent delivery device 37 within space or lumen 38. Aretaining means 8 in housing 36 permits the passage of fluid, keepsdelivery device 37 in lumen 38, and it also prevents device 37 fromblocking outlet 26. Agent delivery device 37, in the illustratedembodiment is an osmotic device, a rate-controlled solid dosage form asdescribed by patentee Felix Theeuwes in United States Patent No.3,845,770. The osmotic device 37, seen in opened section, comprises asemipermeable wall, 37a, such as cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate orcellulose triacetate, that surrounds and forms a compartment 37b. Apassageway 37c extends through semipermeable wall 37a and communicatescompartment 37b and the exterior of osmotic device 37. Compartment 37bcontains an agent formulation 37d, represented by dots, which agentformulation exhibits an osmotic pressure gradient across wall 37a ofdevice 37 against an external fluid that enters chamber 25. The agentformulation can comprise an agent that exhibits an osmotic pressuregradient, or the agent formulation can comprise an agent mixed with anosmotically effective solute, such as sodium chloride, potassiumchloride and the like, that exhibit an osmotic pressure substantiallygreater than the fluid in the chamber 25. In operation fluid that entersin the chamber 25 is imbibed through the semipermeable wall of thedevice into the compartment in a tendency towards osmotic equilibrium ata rate determined by the permeability of the wall and the osmoticgradient across the wall thereby producing a solution that is dispensedthrough the passageway at a rate controlled by the device over aprolonged period of time. The delivery of agent formulation 37d forhomogeneously blending with fluid in chamber 25, is controlled by device37, and its rate of delivery is independent of the rate of fluid flow,and the pH of the fluid in the chamber. Device 37 maintains its physicaland chemical integrity throughout its releasing history. In otherembodiments, not shown, chamber 25 can be manufactured as a one-pieceunit with the delivery device therein, or chamber 25 can be manufacturedwith a closable entrance for admitting the delivery device.Additionally, another embodiment of the invention comprises chamber 25simultaneously acting as a drip chamber while housing the agent deliverydevice. In this embodiment the agent formulation chamber-drip chamber isused to achieve a desired fluid drop rate. For example, the agentformulation chamber-drip chamber can have a fast drop rate for adults,or it can have a slower drop rate for pediatric use. The agentformulation chamber-drip chamber can be made with various sized inletsfor controlling the rate of drip, or the drip can be controlled by aregulating clamp on the tubing conveying fluid thereto The agentformulation chamber-drip chamber can deliver, for example, from 2 to 75drops per milliliter over from 1 minute to 1 hour. More preferably, thetherapist can adjust the rate of flow from 2 to 20 drops per minute, orfor the need of the patient.

The rate performance of the delivery devices used in formulation chamber25 for the purpose of the invention also can be described mathematicallyin terms of the physical and chemical composition of the agent releasesystems. Generally, delivery systems encompassed by this invention arethose for which Q_(R) <0.1Q_(KVO), where Q_(KVO) is the flow of fluidrequired to maintain flow into the veins of an animal in which the flowpath terminates by needle or catheter. This flow is referred to as the"keep vein open" rate, KVO, and it typically is for an adult patientabout 10 to 20 drops per minute, or 0.5 to 1.0 ml per minute Q_(R) isthe maximum rate of fluid flow needed for the delivery system to releaseagent in solution at its label rate. Thus, delivery systems for adultuse require less than 0.05 to 0.1 ml/min to achieve stable deliveryrate. Delivery systems for pediatric use will have a lower absolutelimit, but still satisfy the general criterion of Q_(R) <0.1Q_(KVO).

During operation of device 37 as seen in FIG. 2b, the mass delivery rateof agent from chamber 25 is given by the volume flow rate F expressed byequation (1), of fluid entering chamber 25, times the concentration ofagent C₂, in the chamber with a volume V₂. In the chamber V₂ is thevolume of the total chamber, less the volume V₁ of agent delivery device37. ##EQU1## In the chamber it is assumed that lumen V₂ is stirred byfluid flow to achieve a uniform concentration C₂. The chamber isdesigned to produce a steady state mass flow rate dm₃ /dt, expressed inequation (2), independent of flow rate F leaving the chamber andconveyed to an agent recipient, represented by volume V₃. Thecalculations presented here are: ##EQU2## performed to determine theflow regimen for which the intended end result can be achieved overtime. The calculations are for an osmotic device, designated as 37,containing a mass of agent, m, at the start of a beneficial deliveryprogram. During operation the device delivers at a zero order rate asgiven by equation (3). ##EQU3## wherein K₁ is the permeability of thewall of the delivery device to water, A₁ is the wall area of the device,h₁ is the thickness of the wall, π₁ is the osmotic pressure of saturatedagent solution in the device, π₂ is the osmotic pressure of the solutionin the lumen of the chamber at concentration C₂, and S₁ is thesolubility of agent in volume V₁ in the device. The mass of agent m₂ inthe lumen of the chamber at concentration C₂ is conveyed to the patient.The patient then has a total amount of agent infused of mass m₃ suchthat the mass balance at any time if given by equation (4):

    m.sub.10 =m.sub.1 +m.sub.2 +m.sub.3                        (4)

As a result the mass change in each compartment, the device, the chamberand the patient, is expressed by equation (5). ##EQU4## From equations(3), (5), (6) and (10), equation (11) follows: ##EQU5## wherein h₂ andC₂ are related through Van Hoff's law as shown by equation (12):##EQU6## Equations (11) and (12) result in differential equation (13),from which C₂ follows as a function of time: ##EQU7## and when equation(14) is substituted therein, ##EQU8## equations (15) and (16) follow,##EQU9## and for (16) the solution is given by equation (17): ##EQU10##Equation (17) indicates the time course in which C₂ attains its steadystate value. The steady state value is given by (18), with the flow rate##EQU11## The flow rate into the patient is obtained from (17) and (2)as equation (19): ##EQU12## Equation (19) leads to (1) the minimum flowrate F_(m) needed to achieve a regimen independent of flow, and (2) thetime it takes until the patient receives steady state intravenousadministration. The steady state flow rate achieved with the infuser isgiven by equations (20) or (21): ##EQU13## and the maximum steady stateflow rate is the steady state expressed by equation (22):

    Z.sub.sm =F.sub.1 S.sub.1                                  (22)

the delivery rate from the delivery device. The steady state flow rateas a function of flow F is given by equation (23): ##EQU14## andgraphically represented in FIG. 23, solid line as a function of F/F₁,wherein it can be seen at high flow rates F>F₁, the agent delivery ratefrom the device is independent of fluid flow in the chamber.

Generally the volume flow rates from an osmotic device delivering athigh rates, for example 100 mg/hr, are on the order of 0.05 to 0.2ml/hr. The incoming fluid rate from a container containing a medicalliquid, and referred to as the drip rates from an intravenous gravityfeed system are in the range of from 1 to 400 ml/hr, and for these tworanges the total mass delivery rate is within 80% of the designed rateat all times.

The steady state rate of equation (20) can be expressed relative to thenon-steady state of equation (19) by equation (24): ##EQU15## Underoperating conditions F₁ +F, equation (24), can be expressed as equation(25), ##EQU16## and V₂ /F is a characteristic time of the chamber. It isthe time it takes to clear volume V₂ at incoming flow rate F. Thesesystems are typically designed such that this time is small to reducethe start up time, and the dead volume V₂ usually is less than 1ml.Thus, for the minimum flow rate of 1 ml/hr used in intravenous therapy,the characteristic time would be one hour. Accompanying FIG. 24represents the time it takes to achieve any fraction of a steady statevalue in units of characteristic time, and generally indicating 80% ofthe steady state rate is achieved in 1.5 times the characteristic time.

FIG. 3 depicts agent formulation chamber 25, in opened section,containing another agent releasing device 40, or agent releasing unit,for delivering an agent into an intravenously acceptable fluid thatenters chamber 25. Device 40 is illustrated in opened section and itcomprises an inner mass transfer conductor 41, illustrated as a solidcore and formed of a polymeric material such as curedpolydimethylisoxane, with agent 42 dispersed therethrough. Surroundingmass transfer conductor 41 is an agent release rate controlling membrane43, preferably formed of a polymeric material, such as polyethylene.Both conductor 41 and membrane 43 are permeable to the passage of agent42 by diffusion, that is, agent can dissolve in and diffuse throughconductor 41 and membrane 43. However, the permeability of conductor 41is greater than that of membrane 43, and membrane 43 thus acts as therate controlling member for agent release from device 40. Device 40maintains its physical and chemical integrity throughout the period ofagent delivery. Agent delivery device 40 is disclosed in U.S. Pat. No.3,845,480.

FIG. 4 illustrates the agent formulation chamber, with a section of itswall removed, housing delivery device 44 for delivering an agent at arate controlled by device 44 into a fluid that enters chamber 25. Device44 is seen in opened section and it comprises a reservoir 45 formed of aliquid mass transfer conductor 46 such as a medical oil, a liquidcarrier, permeable to the passage of agent, containing agent 47 such asthe drug phenobarbital. Reservoir 45 is surrounded by a wall 48 formedof an agent or drug release rate controlling material permeable to thepassage of agent 47, such as a polyolefin. The rate of passage of agent47 is lower than the rate of passage through conductor 46, so that agentrelease by wall 48 is the agent release rate controlling step forreleasing agent 47 from device 44. Device 44 maintains its physical andchemical integrity throughout its agent release history. Agent deliverydevice 44 is disclosed in U.S. Pat. No. 3,993,073, which patent isincorporated herein by reference.

FIG. 5 illustrates agent formulation chamber 25, with a part of its wallremoved, housing another device 49 for delivering an agent into a liquidthat enters chamber 25 for forming an intravenously acceptable agentformulation. Device 49 is seen in opened section and it comprises a wall52 surrounding a reservoir 50 containing agent 51. The reservoir isformed of a solid carrier permeable to the passage of agent such ascured polydimethylsiloxane containing the drug diazepam. Wall 52 isformed of a microporous material, the pores of which contain an agentrelease rate controlling medium permeable to the passage of agent 51,for example, formed of a microporous polymer made by coprecipitation ofa polycation and a polyanion. The release of agent 51 is controlled bydevice 49, which device maintains its physical and chemical integrityduring the period of time it is in chamber 25. Device 49 is disclosed inU.S. Pat. No. 3,9093,072, which patent has been incorporated herein byreference.

FIG. 6 is a view of formulation chamber 25 having part of its housingremoved and housing device 53 for delivering an agent into a medicalfluid that enters chamber 25 for forming in situ an intravenouslyacceptable agent formulation solution. Device 53 comprises a matrix 54containing agent 55 distributed therethrough. Matrix 55 is formed from apolymeric material that is non-erodible, that is, it keeps its physicaland chemical integrity over time, and it is permeable to the passage ofagent 55 by the process of diffusion. The rate of agent release from thematrix is determined by the rate the agent dissolves in and passesthrough the matrix by diffusion, so that from the matrix it is the agentrelease rate controlling step. The matrix can possess any shape such asrod, disc and the like that fits into chamber 25. The polymers includepolyolefins such as polyethylene containing muscle relaxants and thelike. Materials useful for manufacturing the devices are disclosed inU.S. Pat. No. 3,921,636.

FIG. 7 is a view of agent formulation chamber 25, in opened view,housing device 56 for delivering an agent into a fluid that enterschamber 25. Device 56 is seen in opened section, and it is formed of amicroporous polymeric material 57 containing agent 58 distributedtherethrough. Matrix 57 is formed of a non-toxic, inert polymer, that isnonerodible and has a plurality of micropores for releasing agent at acontrolled rate to fluid entering chamber 25. Microporous materialsuseful for the present purpose are disclosed in U.S. Pat. Nos. 3,797,494and 3,948,254.

FIG. 8 illustrates agent formulation chamber 25, in opened view, housingdevice 59 for delivering an agent into a medical fluid that enterschamber 25. Device 59 is seen in opened section and it comprises depositof agent solute 61 dispersed in and surrounded substantiallyindividually by a polymer 60 that is impermeable to the passage of agentsolute and permeable to the passage of fluid that enters chamber 25.Agent or a medication solute 61 exhibits an osmotic pressure gradientacross the polymer against fluid that enters chamber 25. Agent 61 isreleased at a controlled rate by fluid from the chamber being imbibedthrough the polymer into the depots to dissolve the solute and generatea hydrostatic pressure in the depots, which pressure is applied againstthe wall of the depots thereby forming apertures that release the agentat a controlled rate over time. Polymer 60 is non-erodible, and device59 can be shaped as a matrix, a rod, a disc, or like shapes. Proceduresand materials useful for manufacturing osmotic bursting delivery systemsare described in U.S. Pat. No. 4,177,256.

FIG. 9 illustrates agent formulation chamber 25, in opened view,containing a delivery system 62 manufactured as a delivery device usefulfor delivering an agent into a medically acceptable fluid passingthrough chamber 25. Device 62 is seen in opened view and it comprises anexterior wall 63 formed of a semipermeable polymer permeable to fluidand substantially impermeable to the passage of agents and solutes. Alayer 64 of an osmotically effective solute, for example sodiumchloride, is deposited on the inner surface of wall 63. Solute layer 64surrounds an inner container 65 formed of a flexible materials that isimpermeable to solute and agent. Container 65 has a passageway 66 fordelivering an agent 67 into a fluid in chamber 25. Device 62 dispensesagent by fluid permeating from chamber 25 through the outer wall 63 tocontinuously dissolve solute 64 in a tendency towards osmoticequilibrium, thereby continuously increasing the volume between wall 63and container 65. This increase causes container 65 to continuouslycollapse and dispense agent 67 from device 62 at a controlled ratethrough passageway 66 to fluid passing through chamber 25. Osmoticallypowered agent dispensing devices are disclosed in U.S. Pat. Nos.3,760,984 and 3,995,631.

In FIGS. 10 and 11 another chamber 25 provided by the invention is seencomposed of a pair of interfitting housing halves 35 and 36 and a ratecontrolled solid agent or drug dosage form 37 contained within the lumen38 of chamber 25. The chamber inlet 24 is in this embodiment thecone-shaped of housing half 35, and the chamber outlet 26 is theconeshaped end of half 36. The inside perimeter of half 36 has a seriesof downwardly inclined flutes 39 on which dosage form 37 rests. Thedosage form is supported by the flutes above the outlet, and is thuskept from blocking the outlet. Dosage form 37 is an osmotic,rate-controlled dosage form as described above and in U.S. Pat. No.3,845,770, which disclosure is incorporated herein by reference. In theillustrated embodiment, dosage form 37 has passageway 37c oriented inthe direction of fluid flow through chamber 25 for lessening theincidence of membrane polarization and to produce release ratespractically unaffected by effluent agent. In this operation the releasepattern is seen in FIG. 23 as represented by the dashed lines. Anotherosmotic agent delivery device, now shown, that can be positioned inchamber 25 is disclosed by patentee Felix Theeuwes in U.S. Pat. No.4,111,202, which patent is incorporated herein by reference. The deviceof this patent comprises a semipermeable wall that surrounds a first andsecond compartment with the first compartment containing an agent andthe second compartment containing an osmotically effective solute thatexhibits an osmotic pressure gradient across the semipermeable wall. Inthis device the compartments are separated by a flexible membrane, andthe device has a passageway that communicates with the compartmentcontaining the agent for its delivery from the device. This device, whenin operation, delivers agent by imbibing fluid from the infuser into thefirst compartment to form a solution containing agent, and into thesecond compartment to form a solution containing the solute whichcontinuously fill the second compartment and expands the membrane intothe first. The agent is delivered through the passageway by the combinedactions of the first and second compartments at a controlled rate over aperiod of time, For this delivery device, like the device describedabove, the mass rate of agent released by the device is substantiallyindependent of the volume flow of intravenous fluid to the patient as itis instead controlled by the mass release of agent form the dosagedevice. This relationship is shown in FIG. 14 in solid line. In FIG. 23the rate of release from the device when passageway 37c is directed inthe path of liquid flow is illustrated in dashed lines.

Agent administration that is independent of intravenous fluid flow rateis extremely advantageous as careful control of the volume flow rate ofintravenous fluid through the formulation chamber is not required.Hence, repeated adjustment of the flow by medical personnel, or the useof expensive, automated flow monitors is not needed. The operation alsohas all the advantages that are associated with the fact that theformulation of agent and intravenous fluid is carried out automaticallyin situ within the chamber. Moreover, since the chamber can bepositioned within the intravenous therapeutic system when needed, theseparation of the agent and the intravenous fluid until administrationprovides significant stability and handling advantages. The presentinvention also eliminates the need to have the agent formulated into aparenteral solution by a pharmacist, and it also eliminates the need forthe agent to be packaged separately from the intravenous fluidcontainer. Another advantage provided by this invention is that theagent dosage delivery device is compatible with conventionalsterilization techniques that are commonly used to sterilize intravenoustherapy systems, so the agent formulation chamber, including the agentdelivery device, may be incorporated into the entire intravenous systemat the time of manufacture and sterilized therewith.

FIG. 12 illustrates another agent formulation chamber designated 25. Inthis chamber the rate-controlled dosage delivery device is not in directpath of the intravenous fluid flow through chamber 25. In thisembodiment chamber 25 includes a pair of hollow interfitting housinghalves 71 and 73. Housing half 71 has an inlet opening or its coneshaped end for tubing 23. The inner surface of half 71 carries a pair ofintegral flanges 74 and 76 that together with a thin microporousmembrane 70 define an enclosed pocket 75 inside the lumen 72 of chamber25. An agent delivery device 37 is contained within the pocket. Device37 is, as described above, a complete rate-controlled form and it mayadditionally act in combination with membrane 70 to enhance the controlof agent into passing fluid. Such combinations, in which an element ofchamber is used with a delivery device, are intended to be within thephrase rate-controlled delivery as used herein. In such combinationsmembrane 70 can serve as a rate-controlling barrier that regulates therate at which the agent enters the mainstream of intravenous fluid flowthrough the chamber As device 37 is a complete rate-controlled form, themembrane acts as a supplemental barrier or as a means for confining thedevice so that it does not block the entrance or exit of chamber 25.Membrane 70 permits the passage of fluid so that as intravenous fluidfills and passes through the chamber, which flow is represented by thestraight arrow in FIG. 12, water from the fluid will diffuse,represented by curved arrows, through the pores of the membrane into thepocket and motivates device 37 to release drug. The released agent willpass from the pocket through the membrane into the mainstream flowthrough chamber 25. The rate at which the agent will enter themainstream will depend on its concentration in the solution within thepocket, the surface area of membrane 70, and the rate of passage of themembrane to agent. In any event, that rate is independent of the overallflow rate of intravenous fluid through chamber 25. Accordingly the agentis formed in situ within chamber 25 and it is administered to thepatient at a rate that is dependent upon the characteristics of thedevice. The microporous membrane 70 may be useful also to prevent agentparticles from entering the flow path, and for providing an extra marginof safety against microorganisms, in the event any may have survived thesterilization procedure for the system.

FIG. 13 shows another agent formulation chamber, generally designated25, in which the dosage form is not in the direct path of theintravenous fluid flow through the chamber. The chamber is particularlyadapted to hold a plurality of the same or different delivery devices.The chamber, like those shown in the other figures, includes a pair ofhollow, interfitting housing halves 80 and 81 that have an inlet openingand outlet opening, now shown, at their respective ends. The insidesurface of half 80 carries a pair of radial flanges 82 and 83 thatextend entirely around the inner circumference of the half. Theseflanges, together with a tubular microporous membrane 84 that isattached at its ends to the flanges, divides the lumen of the chamberinto a main intravenous flow path 85 and an outer concentric pocket 86.A plurality of agent delivery units 37 are contained within the pocket.Membrane 84 and pocket 86 functions in the same manner as membrane 70and pocket 75 of FIG. 12. That is, as intravenous fluid flows throughthe chamber, water from the fluid diffuses through the membrane intopocket 86 and causes the device to release agent. The agent thendiffuses from the pocket through the membrane and into the mainstream ofthe intravenous fluid flow. In instances in which the devices aredifferent, it may be desirable to divide pocket 86 into a plurality ofpockets, one for each device. This may be accomplished with impermeableaxial partitions, now shown, that extend between the inner surface ofthe half, the membrane, and the two flanges. In such instances it may bealso desirable to have membrane 84 formed from segment of differentmicroporous materials, each segment covering a separate pocket. In thismanner different release rates of different agents into the passingintravenous fluid may be effected.

In FIG. 14, formulation chamber 25 is illustrated with a section removedfor depicting the inside of the chamber. The chamber is light weight,disposable and indicated for use in patients requiring intravenousadministration of a fluid containing a beneficial agent, such as anintravenously administrable drug. In FIG. 14 formulation chamber 25comprises a wall body 87 of tube shape and it has a pair of caps 88 and89 for forming a closed chamber containing fluid and a delivery system.Caps 88 and 89 fit chamber 25 and they are preferably made ofself-sealing rubber through which a needle or a hollow spike can beinserted, or they can have an integrally formed tubular extension 90 and91 for receiving an incoming tube. Hollow tube member 90 and 91 arepreferably round for receiving a tube that slides into, or slides overthe member. Formulation chamber 25 is made of a material that ismoisture proof, impermeable to microorganisms, does not adversely affecta drug or a delivery system, is permeable to ionizing rays, and adaptedto house a delivery system and incoming fluids.

The delivery system depicted in formulation chamber 25 comprises amultiplicity of tiny timed pills 92 for the controlled delivery of anagent, including drug, into a fluid entering chamber 25. The tiny pillsare seen in detail in opened section pill 93, and they comprise a coreof drug 94 surrounded by a wall 95 formed of a release rate controllingmaterial. Tiny pills 92 can also comprise encapsulated different drugpresent as separate drug particles. Tiny pills 92 can also comprise drugin an opened porous matrix, or tiny pills 92 can also comprisemicroparticles present in a single core matrix or microparticles presentin a separate supporting matrix for each microparticle. The tiny timespills 92 provide a high membrane surface area for achieving high releaserates of agent for forming an agent solution. The tiny pills releasedrug at a rate of at least 1 nanograms per hour over time into incomingfluid to form the intravenous solution. The total number of tiny pills92 in formulation chamber 25 can be varied as an added means forregulating the amount of agent made available for forming an agentsolution. The materials forming wall 95 can be selected from materialsthat release drug 94 by different physical-chemical mechanisms. Thesemechanisms include erosion, diffusion and osmosis mechanisms. Wall 95when releasing drug by osmosis releases drug by bursting. Drug 94 inthis embodiment is present in the form of an osmotic solute, such as atherapeutically acceptable salt, and it exhibits an osmotic pressuregradient across wall 95 against an external fluid that enters theformulation chamber The membrane materials used to form wall 95 arethose permeable to the passage of an external fluid and substantiallyimpermeable to the passage of drug. Typical materials include a memberselected from the group consisting of cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulosetriacetate, and the like. The osmotic wall can be coated around the drugin varying thickness by pan coating, spray-pan coating, Wurster fluidair suspension coating, and the like. The wall is formed using organicsolvents, including methylene chloride-methanol, methylenechloride-acetone, methanol-acetone, ethylene dichlorideacetone, and thelike. Osmotic wall forming materials, procedures for forming the walland osmotic bursting procedures are described in U.S. Pat. Nos.2,799,241, 3,952,741, 4,014,344 and 4,016,880.

Wall 95 of tiny pills 92 in another embodiment can be made of a drugreleasing material. That is, drug 94 dissolves in the wall or throughpores within the wall and passes through the wall or through said proesat a controlled rate by diffusion over time. Exemplary material usefulfor forming a diffusional wall or a wall with pores includeethylene-vinyl acetate copolymer, ethyl cellulose, polyethylene,cross-linked polyvinyl pyrrolidone, vinylidene chloride-acrylonitrilecopolymer, polypropylene, silicone, and the like. The wall can beapplied by techniques described above, and materials suitable forforming wall 95 are described in U.S. Pat. No. 3.938,515, 3,948,262, and4,014,333.

Wall 95 of tiny pills 92 can be made of bioerodible material thatbioerodes at a controlled rate and releases drug 94 to the fluid inchamber 25. Bioerodible materials useful for forming wall 95 includepolycarboxylic acid, polyesters, polyamides, polyimides, polylacticacid, polyglycolic acid, polyorthoesters, and polycarbonates that erodeto form intravenously acceptable end products. These polymers andprocedures for forming wall 81 are disclosed in U.S. Pat. No. 3,811,444,3,867,519, 3,888,975, 3,971,367, 3,993,057 and 4,138,344. The amount ofdrug present in a tiny timed pill generally is about 10 ng to 50 mg, andthe number of tiny pills in a chamber is about 10 to 1000, preferably atleast 50 to 150. The tiny pills comprising the wall and the inner coreof drug have a diameter of at least 100 microns and, in a presentlypreferred embodiment, a diameter of at least 2000 microns. The tinypills can have one or more coatings of wall-forming materials thereon.The beneficial agent on release by the delivery system is formulated insitu, mixed, added, dissolved, suspended, carried and/or the like, in orby the fluid into a physical-chemical form acceptable for parenteraladministration, including intravenous administration. Chamber 25optionally is equipped with a support 96 for the tiny pills. Support 96can be a film having release rate properties and made of a polymer thatreleases drug from chamber 25. Support 96 can be a microporous polymericmembrane, a sintered glass support, a perforated grid and/or the like.

FIG. 15 illustrates a formulation chamber 25 comprising a wall 97surrounding a lumen 98 having an inlet 99 and an outlet 100. Chamber 98houses a plurality of tiny capsules 101 further seen in opened sectionin capsule 102. Capsule 102 comprises a wall 103 surrounding a mass ofliquid drug 104. The tiny capsules can be made by co-acervationtechnique consisting essentially of forming three immiscible phases, aliquid manufacturing phase, a core material phase and a coating phase.The coating phase is deposited as a liquid on the core material andrigidized usually by thermal, cross-linking or similar techniques toform tiny microcapsules. The capsules made by this technique have anaverage particle size of from several tenths of a micron to 5,000microns and in some embodiments a larger tiny capsule can be usedtherein. Particle size, however, is not critical in the practice of thisinvention. Suitable techniques for preparing tiny microcapsules arereported by Bungenberg de Jone and Kass, Biochem. Z., Vol. 232, pp 338to 345, 1931; Colloid Science. Vol. 11, "Reversible System," edited byH. R. Kruyt, 1919, Elsever Publishing Co., Inc., New York; J. Pharm.Sci., Vol 59, No. 10, pp 1,367-1,376; and Pharmaceutical Science,Remington, Vol. XIV, pp 1,676-1,677, 1970, Mack Publishing Co., Easton,PA. Formulation chamber 25 also contains a film 104 that supports thetiny capsules and which film can also serve a a means for regulating therelease of drug solution from formulation chamber 25.

FIG. 16 illustrates a formulation chamber 25 comprising a wall 105 thatsurrounds an internal lumen 106 with an inlet end 107 and an outlet end108. Chamber 25 houses a multiplicity of hollow fibers 109, with onefiber seen in opened section comprising a wall 110, that can be formedof a semipermeable polymer, a diffusional polymer, a microporouspolymer, a lamina, or a laminate of two or more lamina surrounding alumen 111 containing drug 112. The hollow fibers provide a large exposedsurface area for concomitantly releasing a large amount of agent intothe formulation chamber The hollow fibers can have a length of a fewmillimeters to many centimeter or longer, a diameter or a millimeter orlarger, and the chamber houses at least one hollow fiber to severalhundred or more. The hollow fibers have openings at each end, 113 and114; can be produced from non-cellulosic polymers using melt spinningtechniques using shaped spinnerettes. Hollow fibers can also be producedby spinning an organic solvent cellulosic solution into certainregenerants, n-octanol where the solvent is dialkylacylamide, andn-hexanol where the solvent is dimethyl sulfoxide. The hollow fibers canbe filled with drug by using a solution of drug injected into one openedend of the fiber, by soaking in a drug solution, and the like. Thehollow fibers can release an agent by diffusion, dialysis, osmoticleaching and like techniques. The amount of agent released from thefibers further can be regulated by selecting the dimensions and numberof hollow fibers housed in the formulation chamber. A procedure formanufacturing hollow fibers is disclosed in U.S. Pat. No. 4,086,418.Formulation chamber 25 optionally contains a support 115 for holding thefiber which support permits the passage of drug formulation from chamber25.

FIG. 17 illustrates formulation chamber 25, seen in opened section, andit comprises a wall 116 that surrounds a lumen 117 with an inlet 118 andan outlet 119 for admitting and exiting fluid from chamber 25. Chamber25 houses a multiplicity of fibers 120 containing drug 121, representedby dots. The fibers 120 forming the drug delivery system can be ofnatural or synthetic origin, and they can have a wide variety ofstructures, such as solid, semi-solid, porous, and the like; a varietyof geometric shapes such as round, oval, square, trilobal; variouslengths and cross-sections, and the like. The fibers can functioneffectively as a reservoir by having drug dispersed therethrough.Suitable fibers can be made by conventional fabrication techniques. Forexample, fiber material and drug may be dissolved in a solvent, extrudedthrough small holes of a die and then solidified by standard meltspinning, wet spinning, or dry spinning techniques. In anotherembodiment the fibers can be produced by pumping a melt of fiber anddrug through a spinneret.

With such a method, fiber diameter may be varied from a few tenths to amicron to a millimeter or so by down-drawing, or by up-drawingtechniques,. The lumen of the chamber can house fibers of mixed denier.The fibers forming the reservoir can be filled, saturated, orsemi-filled with drug by immersing, soaking, or the like, and permittingthe desired amount of drug to transfer into the fibers. Other techniquesand drugs for forming fibers are disclosed in U.S. Pat. No. 3,228,887and 3,921,636. The materials forming the fibers can be polyolefins,polyamides, polyurethanes, cellulosic materials, and the like. Fiberprocedures are set forth in Encyclopedia of Science and Technology, Vol.5, pp 263-276, 1971, published by McGraw Hill Co., New York. Chamber 25also contains a membrane 122 for supporting the fibers and it can beformed of a diffusional or porous polymer for cooperating with thefibers for regulating the amount of drug solution infused into apatient.

FIG. 18 illustrates a formulation chamber 25 having a section of itswall 123 removed for depicting the internal space 124 as a means forhousing a beneficial agent delivery system 125. System 125 comprises areservoir formed of an erodible polymer, and a section 126 is removedfor illustrating agent 127 dispersed therein. The erodible polymer canbe a member selected from the group including polyorthoesters,polyorthocarbonates, polyglycolic acid, polylactic acid, polyacetals,polyketals, polyamino acids, and the like. Procedures and erodiblepolymers are disclosed in U.S. Pat. No. 4,180,646; in Int. J. ofPharmaceutics, Vol. 7, pp 1-18, 1980; in Biodegradables and DeliverySystems for Contraception, Chapter 2, edited by E S.E.Hafex and W. A. A.Van Os, published by G. K. Hall, Boston, 1980. Chamber 25 also can havea release rate controlling polymeric film 128 such as cellulose acetate,or the like, and a filter 129. Filter 129 is a conventional filter witha pore 130 having pore size of 0.1 micron to 5 micron, and morepreferable 0.22 micron or 0.45 micron, for removing bacterial andunwanted matter from flowing solution, thereby aiding in maintaining asterile solution.

FIG. 19 illustrates a formulation chamber 25 in opened view comprising awall 131 surrounding an internal space closed at its inlet end with acap 132 and at its outlet end with cap 133. Cap 132 has a tube receivingmember 134 and caps 133 has a tube receiving member 135 for letting afluid into and out of formulation chamber 25. Formulation chamber 25, inits internal space 136, houses a delivery system comprising a pluralityof ion exchange resin particles 137 having a drug 138 ionicallyattracted thereto. The particles, and the like, can vary in size,usually from 10 to 350 mesh. The resins can be homopolymers, copolymers,derivatives thereof, or cross-linked resins. Typical resins include ionexchange resins such as cross-linked styrene-divinyl benzene, and thelike, having drug 138 ionically bonded thereto. Active drug 138 isreleased from resin 137 into fluid that enters the formulation chamberto form in the chamber a drug solution for administering to a patient.The combination comprising the intravenous formulation chamber and thedrug ion exchange member is a useful improvement in intravenous therapy.The improvement in forming the drug fluid formulation in situ comprisesgoverning the combined operation of physical-chemical operation thatcontinuously occur simultaneously in the formulation chamber. That is,the rate of drug fluid formulation is governed by the rate of release ofion drug from the ion exchange combined with the rate of fluid flow andthe drug exchangeable ion concentration in the fluid to yield anintravenously administrable fluid drug formulation. Chamber 25 also canhouse a film 139 that releases the drug formulation and a filter 140having pores 141 for preventing bacteria and unwanted matter fromleaving the formulation chamber . The ion exchange resins are disclosedin U.S. Pat. No. 4,203,440.

The invention, as exemplified by the above figures, provides that agentdelivery devices containing various amounts of an agent or an amount ofdrug can be placed into the formulation chamber. The device can containfrom about 1 mg to 5 g of agent or more, in, for example, 1 to 7 or moredosage units. The device can release agent at a rate of 10 ng/hr up to 2g/hr into the chamber having a volume capacity of least 2 ml up to 250ml, through which intravenous fluid flows at a rate of 1 ml/hr up to 20ml/hr or higher. The term drug is represented by heparin, isoproterenol,and the like.

Agent formulation chamber 25 is a unique component of the parenteral,including intravenous, delivery system both as the chamber alone and incombination with the system. In another embodiment of the inventionformulation chamber 25 contains an intravenously administrablebeneficial agent, and the use of formulation chamber 25 with agenttherein does not require any reconstitution or admixture prior to use.The agent in chamber 25 can be in any pharmaceutical state that forms anagent formulation with the fluid that enters the chamber. Exemplarypharmaceutically acceptable forms include solid, crystalline,microcrystalline, particle, pellet, granule, powder, tablet,spray-dried, lyophilized, and compressed forms that undergodisintegration and dissolution in the presence of an intravenous fluidsuch as compressed particles, compressed powders, compressed granules,friable layers of agent, and the like. Agent formulation chamber 25generally will store an amount of agent for executing a prescribedtherapeutic or beneficial program. That is, an amount of agent for thepreprogrammed, unattended delivery of a therapeutically or abeneficially effective amount of the agent to produce a therapeutic or abeneficial result.

Agent formulation chamber 25 generally can house from about 5 milligramsto 20 grams of agent, or more. In the embodiments wherein chamber 25contains a beneficial agent in the immediately above mentionedpharmaceutically acceptable forms, chamber 25 optionally is equippedwith a release rate controlling membrane, for example a microporouspolymeric membrane, or the like, that governs the rate of release ofagent solution from chamber 25. The membrane can rest on a sinteredglass support, not shown, integrally made into chamber 25; the membranecan be sealed adhesively to the inside wall of chamber 25; fusedthereto; be supported by wall of the chamber pinched inwardly; on a rimin the chamber; or it can be supported or suitably fixed to an end capof chamber 25. Optionally chamber 25 can be equipped with a release ratecontrolling membrane at its inlet for governing fluid flow into chamber25.

FIGS. 20 through 22 illustrate formulation chambers with a sectionremoved for depicting the inside of the chambers containing apharmaceutically acceptable form. In FIG. 20, chamber 25 comprises awall 141 with a section removed at ends 142 and 143. Chamber 25 containsagent 144 that is soluble in intravenously acceptable fluids, and a film145 formed of a material for controlling the flow of fluid and agentfrom chamber 25. Film 145 in a preferred embodiment is formed of anagent release rate controlling polymer, such as a microporous polymerlike a polycarbonate, a semipermeable polymer like cellulose acetate, ora diffusional polymer like ethylene-vinyl acetate copolymer. Thepolymeric film according to the mode of the invention is used in apresently preferred embodiment for governing the rate of release ofsolution containing agent from chamber 25, that is, agent release andfluid flow through chamber 25. Chamber 25 is illustrated with a film atits exit and, optionally, it can have a film at its inlet.

FIG. 21 illustrates a formulation chamber 25, in open view, comprisingagent 146 in particle form, a release rate controlling film 147 such ascellulose acetate or the like, and a filter 148. Filter 148 is aconventional filter with a pore size of 0.1 micron to 5 micron, or more,preferably 0.22 micron or 0.45 micron, for removing bacteria andunwanted matter from the flowing solution, thereby aiding in maintaininga sterile solution. FIG. 22 illustrates formulation chamber 25 made withan internal pocket 149 defining an area for containing agent 150, forexample, the drug ephedrine sulfate. Pocket 149 is formed of a wall 151made of a material such as a diffusional, semipermeable, or amicroporous polymer that permit the passage of medical fluid into pocket149 and agent solution formed therein from pocket 149. In an embodiment,when wall 151 is a semipermeable polymer that divides chamber 25, it canbe provided with a delivery orifice 152 to dispense the agent solutioninto chamber 25. Wall 151 is joined by adhesive, heat sealing, or thelike, to wall 153 of chamber 25. Wall 153 is made of a materialsubstantially impermeable to the passage of agent, medical fluid andagent solution formed therein. In operation fluid enters chamber 25 andthen into pocket 149 wherein it forms a solution containing the agentthat passes into chamber 25 and them is administered therefrom to arecipient. The system in FIG. 22 allows regulation of fluid flowindependently from agent delivery. Delivery is governed by the masstransport characteristics of membrane 151, and fluid flow is governed bya resistance element, for example, a flow regulator in the fluid path.

The novel and useful invention provides a parenteral, includingintravenous, delivery system, a formulation chamber comprising means forsupplying a beneficial agent, and a method for obtaining precise controlof agent release with a parenteral delivery system for administration toa warm-blooded animal. While there has been described and pointed outfeatures of the invention as applied to presently preferred embodiments,those skilled in the art will appreciate that various modifications,changes, additions and omissions in the invention illustrated anddescribed can be made without departing from the spirit of theinvention.

I claim:
 1. A cell comprising:(a) a wall defining a lumen having a firstend and a second end; (b) said first end having means connectible to aparenteral administration set, which set comprises a source of fluid fordelivering the fluid to the cell and an output portion for parenterallyadministering the fluid to a patient; (c) said second end comprisingmeans for connecting to the output portion of said administration set,and wherein; (d) said cell comprises a tablet, which tablet comprises atherapeutic composition formulated in a matrix, which matrix regulatesthe rate at which said therapeutic composition is released into saidfluid when said fluid flows through said cell that is adapted forformulating a therapeutic composition with said fluid.